Dehydroepiandrosterone (DHEA) is a mild androgenic steroid produced by the adrenal cortex and gonads in men and by the gonads in rodents. In all species it is partly under hypothalamo-pituitary control and formed from common steroid precursors. Although DHEA may act as a precursor for more physiologically active androgenic steroids (e.g. testosterone) it is normally secreted as a hormone in its own right. DHEA is rapidly sulphated to DHEA sulphate (DHEAS) before release into the circulation and it is this latter species which constitutes the main circulating form of the steroid. Outside of the CNS DHEAS is itself inactive. To exert physiological effects it must be desulphated by a steroid sulphate sulphatase at the target site and therefore is able to influence local biological events.
Circulating DHEAS levels decline with age (unlike other steroids) and there is some evidence suggesting that exogenous DHEA administration in mice can reverse some of the physiological events associated with the aged phenotype (Daynes et al (1993) The Journal of Immunology, Vol 150: 12, 5219-5230). For example, administration of DHEAS can reverse the increase in IL-6 production in aged mice (Daynes et al (1993) The Journal of Immunology. Vol 150: 12, 5219-5230). In addition, DHEA may regulate insulin sensitivity of adlpocytes and skeletal muscle (Cleary, (1991) P.S.E.B.M. Vol 196: 8-17) However, its major physiological role may be its ability to influence immune responses.
The immune response to antigen is generally either cell mediated (T-cell mediated killing via processed antigens) or humoral (antibody production via recognition of whole antigen). The pattern of cytokine production by T.sub.H cells involved in the immune response can influence which of these response types predominates: cell mediated immunity (T.sub.H1) is characterised by high IL-2 and IFNg but low IL-4 production, whereas in humoral immunity (T.sub.H2) the pattern is low IL-2 and IFNg but high IL-4, IL-5, IL-10. Since the secretory pattern is modulated at the level of the secondary lymphoid organ then pharmacological manipulation of the specific TH cytokine pattern can influence the type and extent of the immune response generated.
It is well established that administration of exogenous glucocorticoids to ovalbumin-sensitised mice (and other species) induces immunosuppression in which spleen cells show a reduced capacity to secrete IL-2 but are able to enhance IL-4 secretion upon antigen challenge. In contrast, DHEA or DHEAS administration markedly augments IL-2 and IFNg secretion without affecting IL-4 release (Daynes et al (1990) Eur. J. Immunol. 20 793-802). When DHEA and dexamethasone are co-administered, the DHEA effect predominates which is consistent with DHEA acting as an anti-glucocorticoid in this and other systems (Daynes et al (1990) Eur. J. Immunol. 20 793-802), Browne et al (1992) The American Journal of the Medical Sciences 303 No. 6, 366-371 and Blauer et al (1991) Endocrinology 129 No. 6, 3174-3179). These differing responses of glucocorticoids and DHEA are indicative of T.sub.H2 and T.sub.H1 type cytokine patterns respectively, suggesting that they can differentially influence immune responses. Similar effects are seen if spleen cells from sensitized animals are treated with anti-CD3 in the presence of either DHEA, DHEAS or dexamethasone (Daynes et al (1990) J. Exp. Med. 171 979-996).
The immunostimulatory response to biologically inactive DHEAS indicates that there is conversion by steroid sulphate sulphatase within the confines of the secondary lymphoid tissue to the active DHEA. The location of the converting enzyme (steroid sulphate sulphatase) is within the antigen presenting cells (APC) since in purified T cell preparations treated with anti-CD3 antibody. DHEA but not DHEAS could enhance IL-2 production. However, if macrophages were added to the system both steroid types could elicit the increased IL-2 response (Daynes et al (1990) J. Exp. Med. 171 979-996). Hence the pattern of cytokine secretion of T.sub.H cells can be regulated within the secondary lymphoid microenvironment under the influence of adrenal steroids with DHEA promoting cell mediated (T.sub.H1) type responses. This effect would be counter-regulatory to the normal effect of endogenous glucocorticoids (inhibiting cell-mediated type responses). Indeed, a high affinity binding site for DHEA has been described in murine T cells that is distinct from the T-cell glucocorticoid receptor (Melkle et al (1992) J. Steroid Biochem. Molec. Biol. 42 No. 3/4, 293-304). Furthermore, many of these observations of steroid effects on immune responses in mice have also been demonstrated using human cells (Suzuki et al (1991) Clinical Immunology and Immunopathology 61, 202-211).
T.sub.H1 and T.sub.H2 -dependent responses show some degree of anatomical compartmentalisation; those lymphoid areas draining non-mucosal sites (e.g. spleen, peripheral lymph nodes) generate predominantly T.sub.H1 cytokine secreting patterns and those draining mucosal sites (eg Peyer's patches) show T.sub.H2 type responses. Indeed, anti-CD3-treated cells taken from spleen, peripheral lymph nodes or Peyer's patches from sensitised mice treated with DHEA show typical increased IL-2 and IFNg secretion but only spleen cells or peripheral lymph node cells do so when DHEAS was the treatment. In fact cells from Peyer's patches do not increase IL-2 production following DHEAS treatment but show a high IL-4 and low IL-2 secretion typical of a T.sub.H2 (and glucocorticoid) type response. This differential influence of DHEA on T.sub.H cell cytokine production correlates with the presence of DHEAS sulphatase in these areas; for example, brachial and axially lymph nodes (non-mucosal) have 6.times. the DHEAS sulphatase activity than Peyer's patches (mucosal; (Daynes et al (1990) J. Exp. Med. 171 979-996). Hence, in lymphoid areas where generally cell mediated immune responses take place then T cell cytokine production is influenced by locally produced DHEA whereas in areas governing humoral responses. DHEA has less influence allowing effects of circulating glucocorticoids to predominate. Any effects of DHEA are relatively discrete since it is rapidly resulphated on the first-pass through the liver. It follows therefore that in diseases where increased cellular immunity to specific antigens is pathological (e.g. autoimmunity) then a reduction in the influence of DHEA on these responses should lead to a state of relative immunosuppression with humoral immunity being spared.
We believe that inhibition of steroid sulphate sulphatase within the macrophage or other antigen presenting cells would lead to a decreased ability of sensitised T cells to mount a T.sub.H1 (high IL-2, IFNg low IL-4) response. The normal regulatory influence of other steroids such as glucocorticoids would therefore predominate.
Inhibitors which prevent the normal physiological effect of DHEA or related steroids thereby prevent DHEA or related steroids acting as an anti-glucocorticoid and consequently reveal an endogenous glucocorticoid-like effect. Since glucocorticoids can act on inflammatory processes as well as immune processes this endogenous glucocorticoid-like effect may therefore be manifested as an anti-inflammatory response.